Ebola (EBOV) and Marburg (MARV) viruses belong to the family Filoviridae and can cause fatal hemorrhagic fevers characterized by widespread tissue destruction with an incubation period of 4-14 days. Because of the safety concerns, these viruses are designated as the biosafety level 4 agents. Currently there is no effective vaccine or therapeutic treatment against filoviral infection and pathogenesis in humans. Africa has recently suffered a lethal EBOV epidemic, which has spilled over to other continents, including the United States, underscoring the urgency of antiviral drug discovery and development. This application defines a plan to develop potent, small molecule inhibitors, which block entry of EBOV. We have identified compounds that inhibit entry of infectious EBOV/MARV (IC50 values ?25 M). These hit compounds exhibit selectivity for EBOV/MARV entry. The overall objective of this Phase I application is to develop these inhibitors as potential anti-EBOV therapeutics. This application will focus on the following three specific aims: (1) Synthesize structurally diverse analogs of the anti- Ebola CBS1111 hit series based on structure-activity relationships (SARs) to improve potency and selectivity. (2) Validate the lead inhibitor candidates in the infectious assay and investigate the mechanism of action (MOA) of the EBOV inhibitors. (3) Select EBOV inhibitors with in vitro ADME properties suitable for i.v. and oral dosing.